Exploring the role of central nervous system myelination in circuit function and behaviour
Madden, Megan Elizabeth
Activity-mediated myelination, the adjustment of myelin morphology in response to neuronal activity, has been proposed as a novel mechanism of central nervous system (CNS) plasticity. As a key regulator of conduction velocity, adaptations in myelin structure have the potential to exert spatiotemporal control over action potentials across neurons of a given circuit, in turn influencing circuit function and behaviour. Despite a breadth of evidence supporting this hypothesis, a definitive conclusion has been hindered by the technical difficulties of assessing circuit activity in parallel with myelin morphology and behaviour in vivo. Using larval zebrafish as a model, this study investigated the effect of disrupting the normal program of CNS myelination on the development of locomotor behaviour. CRISPR/Cas9 mutagenesis of Myelin Regulatory Factor (Myrf) gene, encoding for a transcription factor vital for CNS myelination, was used to create a CNS specific model of hypomyelination. Larvae from Myrf heterozygous in-crosses were then tested across a suite of behavioural assays, allowing the measurement of detailed kinematic parameters during spontaneous and stimulus-driven responses. Myrf homozygous mutants displayed a 66% reduction in the number of myelinated axons in the spinal cord along with reduced gene expression of myelin basic protein (Mbp). Unexpectedly, heterozygous animals exhibited precocious myelination of small caliber axons, resulting in a 53% increase in the number of myelinated axons. This finding was associated with a subtle upregulation of Mbp gene expression. Subsequent behavioural analysis revealed that Myrf homozygous mutants demonstrated a significant delay in the latency to perform acoustic startle responses. Interestingly, both homozygous and heterozygous mutants exhibited an increase in the frequency of high velocity swim bouts performed during spontaneous swimming, driven by subtle adjustments in tail kinematics. The findings of this study support a role for myelination in the control of action potential timing across defined circuits of the CNS and suggest that a balance of myelination is important for the function of more complex circuits such as those controlling swim speed. Future work, using in vivo electrophysiology and functional imaging, will interrogate how neuronal activity is altered in the circuits underlying these behaviours. Together, these findings will advance our understanding of the role that CNS myelination plays in circuit function and behaviour.